title: Comparative modulation by 3 alpha,5 alpha and 3 beta,5 beta neurosteroids of GABA binding sites during avian central nervous system development.
abstract: Neurosteroids are endogenous Central Nervous System (CNS) compounds which act mainly by allosteric modulation of the GABAA receptor complex. The presence of a 3 alpha-hydroxyl group and a 5 alpha-hydrogen atom have been found to be essential structural requirements for biological activity in mammals. In the present work we report the enhancing activity on [3H]GABA binding to its receptor sites in chick optic lobe produced by progesterone metabolites 3 alpha-hydroxy,5 alpha-pregnan-20-one (3 alpha,5 alpha-P) and 3 beta-hydroxy,5 beta-pregnan-20-one (3 beta,5 beta-P). Both steroids were found able to enhance [3H]GABA binding along ontogeny, displaying a similar profile at early developmental stages, while in adulthood 3 alpha,5 alpha-P had greater potency (EC50 0.22 microM) and enhancing effect (Emax: 122%). In adult synaptic membranes, the two compounds displayed a complex interaction with the GABAA receptor, disclosed by a Schild plot with slope below one and an incomplete displacement of 3 alpha,5 alpha-P by its 3 beta,5 beta isomer. Such complexity could be related to the steroidogenic profile in avian CNS, with 5 alpha-reduced progesterone metabolites present since early development, while 3 alpha,5 alpha-P is found only in adulthood. Bearing in mind differences between avian and mammalian steroidogenic profiles and the relevance of 5 beta-steroids in early avian development, we propose that 3 beta,5 beta-P, instead of the classical potent 3 alpha,5 alpha-steroids, may be the endogenous modulator of GABAergic activity in developing avian brain.
authors.affiliation: Instituto de Biología Celular y Neurociencias, Facultad de Medicina, Universidad de Buenos Aires, Paraguay, Argentina.
authors.forename: M S
authors.initials: MS
authors.lastname: Viapiano
authors.forename: S
authors.initials: S
authors.lastname: Fiszer de Plazas
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D002642:Chick Embryo; D007536:Isomerism; D009899:Optic Lobe, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D011280:Pregnanolone / Q000494:pharmacology*; D018079:Receptors, GABA / Q000187:drug effects; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone